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High CDC20 levels increase sensitivity of cancer cells to MPS1 inhibitors

Siqi Zheng1, Linoy Raz2, Lin Zhou1

  • 1European Research Institute for the Biology of Ageing, University of Groningen, 1, Antonius Deusinglaan, 9713 AV, Groningen, The Netherlands.

EMBO Reports
|January 21, 2025
PubMed

Insights

Spindle assembly checkpoint (SAC) inhibitors are sensitive to high CDC20 expression. This sensitivity is linked to aneuploidy, a cellular vulnerability that shortens metaphase and increases mitotic errors, enhancing drug efficacy.

Area of Science:

  • Cell Biology
  • Cancer Therapeutics
  • Molecular Oncology

Background:

  • Spindle assembly checkpoint (SAC) inhibitors are novel drugs that disrupt chromosome segregation, leading to chromosomal instability (CIN) and cell death.
  • The precise molecular determinants of cellular sensitivity to SAC inhibitors remain unclear.
  • Previous research indicated that aneuploid cancer cells exhibit heightened sensitivity to SAC inhibition.

Purpose of the Study:

  • To investigate the molecular drivers of sensitivity to SAC inhibition, particularly by MPS1 inhibitors.
  • To elucidate the role of CDC20, a key activator of the anaphase-promoting complex (APC/C), in mediating cellular responses to SAC inhibitors.
  • To explore the relationship between aneuploidy, CDC20 expression, and sensitivity to SAC inhibition therapy.

Main Methods:

  • Investigated the impact of CDC20 expression levels on cellular sensitivity to SAC inhibitors.
  • Utilized MPS1 inhibitors as a model for SAC inhibition.
  • Analyzed metaphase duration, mitotic error rates, and CIN induction in response to CDC20 modulation and SAC inhibition.
  • Compared CDC20 expression and SAC inhibitor sensitivity in aneuploid versus euploid cancer cells.

Main Results:

  • Sensitivity to MPS1 inhibitors is predominantly determined by CDC20 expression, with a greater effect than APC/C itself.
  • Depletion of CDC20 prolongs metaphase, reduces mitotic errors, and decreases sensitivity to SAC inhibition.
  • Aneuploid cells exhibit higher basal CDC20 levels, leading to shorter metaphase durations and increased susceptibility to SAC inhibitor-induced CIN.

Conclusions:

  • High CDC20 expression is a key molecular feature predicting sensitivity to SAC inhibition therapy.
  • Aneuploidy-induced elevation of CDC20 creates a cellular vulnerability that enhances the efficacy of SAC inhibitors.
  • Findings suggest CDC20 as a potential biomarker for patient stratification in SAC inhibitor-based cancer treatments.
Keywords:
AneuploidyCancerCell CycleChromosomal InstabilitySpindle Assembly Checkpoint (SAC)

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